Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease

Neural injury leads to inflammation and activation of microglia that in turn may participate in progression of neurodegeneration. The mechanisms involved in changing microglial activity from beneficial to chronic detrimental neuroinflammation are not known but reactive oxygen species (ROS) may be in...

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Veröffentlicht in:	Glia Jg. 58; H. 5; S. 588 - 598
Hauptverfasser:	Rojo, Ana I., Innamorato, Nadia G., Martín-Moreno, Ana M., De Ceballos, María L., Yamamoto, Masayuki, Cuadrado, Antonio
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.04.2010
Schlagworte:	Analysis of Variance Animals Antigens, Differentiation - metabolism Brain - metabolism Brain - pathology Calcium-Binding Proteins - metabolism CD11b Antigen - metabolism Cell Line, Transformed Culture Media, Conditioned - pharmacology Cyclooxygenase 2 - metabolism Cytokines - metabolism Disease Models, Animal Dopamine - metabolism Dopamine Plasma Membrane Transport Proteins - metabolism Flow Cytometry - methods Gene Expression Regulation - drug effects Gene Expression Regulation - physiology Glial Fibrillary Acidic Protein - metabolism Gliosis - etiology heme oxygenase-1 Inflammation - etiology Inflammation - metabolism innate immune system Leukocyte Common Antigens - metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Microfilament Proteins Microglia - physiology MPTP Poisoning - complications MPTP Poisoning - pathology neurodegenerative diseases Neurons - chemistry Neurons - drug effects Neurons - metabolism NF-E2-Related Factor 2 - deficiency NF-E2-Related Factor 2 - metabolism Nitric Oxide Synthase Type II - metabolism Reactive Oxygen Species - metabolism Tyrosine 3-Monooxygenase - metabolism
ISSN:	0894-1491, 1098-1136, 1098-1136
Online-Zugang:	Volltext
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Zusammenfassung:	Neural injury leads to inflammation and activation of microglia that in turn may participate in progression of neurodegeneration. The mechanisms involved in changing microglial activity from beneficial to chronic detrimental neuroinflammation are not known but reactive oxygen species (ROS) may be involved. We have addressed this question in Nrf2‐knockout mice, with hypersensitivity to oxidative stress, submitted to daily inoculation of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) for 4 weeks. Basal ganglia of these mice exhibited a more severe dopaminergic dysfunction than wild type littermates in response to MPTP. The amount of CD11b‐positive/CD45‐highly‐stained cells, indicative of peripheral macrophage infiltration, did not increase significantly in response to MPTP. However, Nrf2‐deficient mice exhibited more astrogliosis and microgliosis as determined by an increase in messenger RNA and protein levels for GFAP and F4/80, respectively. Inflammation markers characteristic of classical microglial activation, COX‐2, iNOS, IL‐6, and TNF‐α were also increased and, at the same time, anti‐inflammatory markers attributable to alternative microglial activation, such as FIZZ‐1, YM‐1, Arginase‐1, and IL‐4 were decreased. These results were confirmed in microglial cultures stimulated with apoptotic conditioned medium from MPP+‐treated dopaminergic cells, further demonstrating a role of Nrf2 in tuning balance between classical and alternative microglial activation. This study demonstrates a crucial role of Nrf2 in modulation of microglial dynamics and identifies Nrf2 as molecular target to control microglial function in Parkinson's disease (PD) progression. © 2009 Wiley‐Liss, Inc.
Bibliographie:	FPU fellowship of Universidad Autónoma of Madrid Spanish Ministry of Science and Innovation - No. SAF2007-62646 ArticleID:GLIA20947 ark:/67375/WNG-7LM38GG8-2 istex:C2FD69B7B8C27492BD436920C88B658D0F43E23F Ana I. Rojo and Nadia G. Innamorato should be considered as first authors. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0894-1491 1098-1136 1098-1136
DOI:	10.1002/glia.20947